ABSTRACT Infection with the malaria parasite Plasmodium falciparum leads to widely different clinical conditions in children ranging from mild flu-like symptoms to coma and death. Despite the immense medical implications, the genetic and molecular basis of this diversity remains largely unknown. We hypothesize that parasites residing in the human host have needed to adapt to this specialized environment that varies in temperature, substrate and immune response. To characterize parasite biology we have utilized whole genome analysis of the parasite from fresh blood samples of infected patients. With this approach we have identified three biologic states of the parasite when it resides in the human host. One of these in vivo states correlates highly to the laboratory grown transcriptional profile, and now we have identified two novel states. The biological basis of these states can be interpreted by comparison with an extensive compendium of expression data in the yeast, Saccharomyces cerevisiae. The three states in vivo closely resemble (i) active growth based on glycolytic metabolism the in vitro like state; (ii) a starvation response accompanied by oxidative phosphorylation; and (iii) an environmental stress response. The results reveal a previously unknown physiological diversity in the in vivo biology of the malaria parasite, in particular, evidence for functional mitochondria in the asexual stage parasite, and point to in vivo and in vitro studies to determine how this variation may impact disease manifestations and treatment. This work highlights the importance of working with human samples to explore clinically relevant parasite biology. Through further clinical studies we propose to 1) identify the host factors that are associated with these novel biologic states 2) identify parasite biology that is specifically found in severe disease 3) test environmental responses of the parasite under controlled conditions using the in vitro model. We are developing a completely novel model for the host pathogen interaction in this parasite. The clinical studies inform the in vitro model and conversely, results of this model can then be tested prospectively in the clinical studies. Furthermore we have developed team of leaders in clinical malaria, computational biology and molecular biology to combine their skills to further our understanding of disease. The long term goal is to identify parasite biology that can be targeted to reduce individual and global health burden of Plasmodium falciparum. Plasmodium falciparum causes infections in humans which range from asymptomatic to highly severe illness often leading to death. Why some patients have severe disease and others are completely well remains poorly understood, and this may be related to specialized parasite biology that occurs in humans. Through the use of genomics, we have identified completely new parasite biology when it resides in humans and this project will determine if this novel biology is related to differences in disease outcomes. This study brings together experts in computational biology and malaria epidemiology to develop clinically relevant models of parasite biology to inform disease interventions to reduce the impact of malaria infection on individual and global health.